Chitin is contained in the exoskeleton of crustaceans such as crab, shrimp, krill, etc. and insects, as the constituent components thereof, and is a naturally occurring basic polysaccharide present in nature in widespread manner. The chitin having a linear chain bonded with N-acetyl-D-glucosamine and chitosan produced through the deacetylation of chitin have been neglected and left alone as unused biological resources for a long period of time. In recent years, however, the absence of toxicity and the physico-chemical properties have been drawing attention, leading to the progress in the active research works for effective application of chitin and chitosan. Thus, expectation has been directed toward the application thereof in a wide variety of fields, for example, as coagulants, ion exchangers, enzyme immobilizing agents, raw materials for hair cosmetics, medicinal materials, food additives, soil modifiers, etc. Chitosan, in particular, is promising because it has advantages, for example, in that it is readily dissolved in dilute hydrochloric acid, aqueous solutions of organic acids and the like, and that the glucosamine residue constituting the molecular chain is a high molecular electrolyte having a free primary amine group (--NH.sub.2).
In the field of pharmaceutical products, alternatively, investigation has been carried out toward a preparation technique for advancing a pharmaceutical preparation to infragastrointestinal tract such as the lower part of small intestine, large intestine, etc., while suppressing the release of the preparation in stomach and the upper part of small intestine after the oral dosage thereof.
Because physiologically active polypeptide hormones such as insulin and calcitonin are water-soluble, high molecular compounds readily decomposed via intestinal proteases such as gastric juice, pepsin and trypsin, the development of an oral pharmaceutical preparation of a type released at infragastrointestinal tract is significant so as to make the polypeptide hormones absorbed at infragastrointestinal tract without the decomposition via the aforementioned proteases. The development is also significant from the respect that pharmaceutical agents effective for diseases of infragastrointestinal tract, such as ulcerative colitis and Chron's disease, be administered directly to the lesions without the occurrence of side effects.
The aforementioned various pharmaceutical agents in the form of parenteral administration have been developed, but they have drawbacks in not only practical inconvenience of complex procedures but also heavy burdens to patients. From such standpoint, the agents are desirably in the form of oral administration as possible.
In conventional oral pharmaceutical preparations of a type released at infragastrointestinal tract, generally, the surface thereof is film coated with a polymer compound dissoluble at a higher pH, and the resulting thickness serves to adjust the absorption site thereof. However, problems have been suggested in that the pH level in gastrointestinal tract varies depending on individuals and that the variation in the site where such pH-dependent preparations as those described above are degraded readily occurs, depending on individuals. If such preparations are degraded, for example, at the upper part of small intestine to release the pharmaceutical agents thereof, some of the agents (for example, the aforementioned polypeptides and the like) may be decomposed without exhibiting the drug efficacy. If the pH value in large intestine is declined because of the metabolism via intestinal bacteria or the like, the coating film provided for the preparations is not dissolved, resulting in no release of the pharmaceutical agents and no exhibition of pharmacological actions. Hence, the preparations are excreted as they are. Proposition has been made of a technique comprising using a polymer film degradable via the bacteria in large intestine and degrading a pharmaceutical preparation in large intestine, but the technique has problems in that such pharmaceutical preparation also causes the variation in the degradation time, depending on the individual difference in the bacteria in large intestine and that the degradation of the polymer film requires a long period of time.
The present invention has been achieved in such circumstances. It is an object of the present invention to provide an optimum form of an oral pharmaceutical preparation of a type released at infragastrointestinal tract by effectively utilizing chitosan.